In recent years, there has been enormous interest in developing “humanized” mouse models as tools for the study, treatment and prevention of human disease. Humanized mice are typically either immune-deficient mice into which human cells are injected and then coaxed to engraft in vivo via regenerative stimuli, or they may be chimeric mice genetically-engineered to express human genes. The explosion of conference meetings sponsored by both academic and pharmaceutical efforts has highlighting the rapid growth of the humanized mouse field. Within basic research settings, humanized mice have been critical to our understanding of many human biological processes that are not easily recapitulated in cell culture. For example, hematopoetic stem cell engraftment in mouse lymphoid organs has allowed researchers to study dynamics of the human immune system, including responses to infectious diseases that do not infect laboratory animals (See e.g., Baenziger et al. (2006) Proc Natl. Acad. Sci. USA. 103(43): p. 15951-6; Ishikawa et al. (2005) Blood 106(5): p. 1565-73; and Shultz et al. (2007) Nat. Rev. Immunol. 7(2): p. 118-30.). Human tissues implanted into mice have also led to greater understanding of organogenesis, carcinogenesis and metastasis (See e.g., Kuperwasser et al. (2004) Proc. Natl. Acad. Sci. USA. 101(14): p. 4966-71; and Kuperwasser et al. (2005) Cancer Res. 65(14): p. 6130-8.). Within pharmaceutical settings, transgenic mice expressing single human liver detoxification enzymes or transcription factors have allowed researchers to better understand human drugresponse pathways (See e.g., Xie and Evans (2002) Drug Discov. Today 7(9): p. 509-15.). Based on these promising findings, humanized mouse programs have been initiated within many pharmaceutical companies towards the development of tools for pre-clinical drug-testing, disease models (e.g., infectious disease models) and the development of novel therapies, diverse humanized mouse applications including drug testing, disease models and the development of novel therapies
Despite these advances, the generation of humanized and chimeric mice is an inherently inefficient process with limited scalability and thus limited widespread utility. Currently, approaches for creating humanized mice require complex transgenics (to model single human genes) and/or cell transplantation protocols (to model whole human organ systems). In the case of the cell transplantation approach, manipulation of the host is often required to provide a sufficient repopulation advantage to transplanted cells. For example, injected hepatocytes home to, engraft and repopulate a mouse liver only in the setting of genetically-induced host liver injury (See e.g., Azuma et al. Nat. Biotechnol. 25(8): p. 903-10; and Tateno et al. (2004) Am. J. Pathol. 165(3): p. 901-12.). Even with this repopulation advantage, the time window required to permit cell engraftment and expansion is lengthy (several weeks to months) and the overall engraftment efficiency among injected animals low (16% injected animals). Thus, a new model which mitigates the need for repopulation stimuli—and which can be generated rapidly and reproducibly among diverse animal backgrounds—promises to significantly advance the commercial utility of humanized mouse models for studying human biology and human disease.